This proposal develops solid support methodology for the synthesis of natural products and their analogs. Multiple component condensation reactions on solid support offer a powerful strategy for compound synthesis in a single chemical reaction. Applied to solid support, these reactions afford multi-milligram quantities of thousands of compounds of high purity and in high chemical yields. These transformations are carried out in a spatially addressable fashion using a single-well single-compound format in which the chemical structure of every member of the library is known. Structure activity relationship (SAR) studies related to these compounds should provide information on establishing their minimum pharmacophore and improving their potency. Three series of natural products have been identified which test this strategy. Successful application of this approach should have wide applicability in other target areas. The solution total synthesis and solid support syntheses of each natural product and related strategies for solid support analog development are presented for the following: Part I. Carzinophilin/azinomycin B and azinomycin A are potent antitumor agents which have been extensively studied in our laboratories. Azinomycin B cross-links B-DNA in vitro in the major groove. A Passerini condensation has been successfully applied to the construction of an initial compound library and preliminary cytotoxicity data suggests a minimum pharmacophore. Described herein is the massively parallel solid support synthesis of carzinophilin analogs. Part II. Myriocin and the related mycesteracins A-E are immunosuppressive agents. In a preliminary mixed lymphocyte assay, these compounds were 10- to 100- fold more potent than the clinically useful cyclosporin A. Two routes are proposed for the synthesis of the natural product and analogs, the first involving the alkylation of serine-derived enolates, and the second using an Ugi four-component condensation. Part III. Hapalosin is a potent cancer multiple drug resistance (MDR) reversing agent. This twelve-membered ring depsipeptide represents a new structure class of MDR P-glycoprotein inhibitors. We envision as a key synthetic step an intramolecular Passerini condensation, serving the dual purpose of cyclizing the depsipeptide and introducing the butyric acid residue. A solid-phase version should provide a powerful tool for the generation of analogous structures.